Contribution of infiltrating macrophages on synaptic function after TBI

浸润性巨噬细胞对 TBI 后突触功能的贡献

• 批准号: 8828464
• 负责人: Susanna Rosi
• 金额: $ 23.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828464
• 关键词: Acute; Affect; Alzheimer' s Disease; Animal Model; Animals; Appearance; Behavioral; Blood; Bone Marrow; Brain; Brain Diseases; CCL2 gene; CX3CL1 gene; Cell Surface Receptors; Cell surface; Cells; Cessation of life; Characteristics; Chronic; Chronic Phase; Cognitive; Cortical Contusions; Data; Dementia; Development; Direct Costs; Discrimination; Disease; Disease Progression; Environmental Risk Factor; Event; Evolution; Facilities and Administrative Costs; Functional disorder; Genetic; Genotype; Goals; Hippocampus (Brain); Hour; Human; Immune; Immune response; Immune system; Impaired cognition; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Kinetics; Knowledge; Lead; Lesion; Life; Mechanics; Mediator of activation protein; Mental Health; Microglia; Modeling; Modification; Molecular; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Pathogenesis; Pathogenicity; Pathology; Pattern; Peripheral; Pharmacological Treatment; Phase; Phenotype; Play; Process; Report (document); Research; Risk; Risk Factors; Role; Signal Transduction; Synapses; Techniques; Testing; Time; Tissues; Traumatic Brain Injury; United States; Work; base; chemokine receptor; cognitive function; controlled cortical impact; cytokine; design; disability; falls; genetic manipulation; inhibitor/antagonist; injured; macrophage; migration; monocyte; neuroinflammation; neuropathology; neurotoxic; new therapeutic target; novel; public health relevance; response; response to injury; synaptic function

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases, including Alzheimer's disease (AD) and numerous recent reports document the development of dementia after TBI. Following the initial mechanical insult, TBI activates a cascade of molecular signaling events that can result in neurodegenerative sequelae, namely cognitive dysfunction. One of the most pronounced responses following TBI is the induction of multiple signaling mediators associated with neuroinflammation, consistently attributed to the activation of the innate immune system. Inflammation is a vital host response to injury, however excessive and unchecked propagation of inflammation can be deleterious to primarily unaffected tissues. Recent work in both humans and various animal models has shown that microglia, the brain's resident immune cells, can remain in an activated state for years after the initial insult. Despite consistent findings implicating the deleterious effects of chronically activated microglia in the brain, little is know about the role of the peripheral innate immune response and its interface with CNS tissues following TBI. Recent work has shown that cell surface expression of Ly6C and CCR2 is characteristic of an inflammatory subpopulation of bone marrow derived blood circulating monocytes. However, there is still a gap in the current knowledge as to the role and function of Ly6ChiCCR2+ monocytes in the propagation of TBI- induced pathology. The ultimate goal of this proposal is to elucidate the functional contribution of this cell subpopulation on TBI-induced neuroinflammation, as well as synaptic and cognitive dysfunction. Aim 1. Will examine if genetic and pharmacological deletion of CCR2 signaling ameliorates TBI-induced synaptic and cognitive dysfunction. TBI will be induced using controlled cortical impact on both wild type and CCR2RFP/RFP mice. We will examine hippocampal-dependent cognitive function as well as homeostatic synaptic function, 28 days after injury. Preliminary studies indicate that CCR2 deletion abrogates TBI-induced hippocampal cognitive dysfunction compared to WT mice. Aim 2. Will determine the temporal kinetics and inflammatory profile of TBI-induced Ly6ChiCCR2+ monocytes/macrophages into the brain parenchyma. TBI will be induced as in Aim 1 except using CX3CR1+/GFPCCR2+/RFP mice. Multiple time points following injury will be examined to include acute, subacute, and chronic phases. Preliminary data shows that 48 hours after injury, TBI-treated mice had a significant increase in macrophage infiltration and that a specific subset of those resembled resident microglia. Our studies will provide critical and novel information in regard to the contribution of peripheral macrophage accumulation in the pathogenicity of TBI-induced neuroinflammation and potentially a novel therapeutic target and optimal time point for its treatment.

描述（由申请人提供）：创伤性脑损伤（TBI）是多种神经退行性疾病（包括阿尔茨海默病（AD））发展的主要危险因素，并且最近的许多报告记录了 TBI 后痴呆的发展。在最初的机械损伤之后，TBI 会激活一系列分子信号事件，从而导致 神经退行性后遗症，即认知功能障碍。 TBI 后最显着的反应之一是诱导与神经炎症相关的多种信号传导介质，这始终归因于先天免疫系统的激活。炎症是宿主对损伤的重要反应，但是炎症的过度和不受控制的传播可能对主要未受影响的组织有害。最近对人类和各种动物模型的研究表明，小胶质细胞（大脑的常驻免疫细胞）在最初的损伤后可以保持激活状态数年。尽管一致的研究结果表明大脑中长期激活的小胶质细胞会产生有害影响，但人们对创伤性脑损伤后外周先天免疫反应的作用及其与中枢神经系统组织的相互作用知之甚少。最近的研究表明，Ly6C 和 CCR2 的细胞表面表达是骨髓来源的血液循环单核细胞炎症亚群的特征。然而，目前对于 Ly6ChiCCR2+ 单核细胞在 TBI 诱导病理传播中的作用和功能的认识仍然存在空白。该提案的最终目标是阐明该细胞亚群对 TBI 诱导的功能贡献 神经炎症，以及突触和认知功能障碍。 目标 1. 将检查 CCR2 信号传导的遗传和药理学缺失是否会改善 TBI 诱导的突触和认知功能障碍。将通过对野生型和 CCR2RFP/RFP 小鼠的受控皮质影响来诱导 TBI。我们将在受伤后 28 天检查海马依赖性认知功能以及稳态突触功能。初步研究表明，与 WT 小鼠相比，CCR2 缺失消除了 TBI 诱导的海马认知功能障碍。 目标 2. 将确定 TBI 诱导的 Ly6ChiCCR2+ 单核细胞/巨噬细胞进入脑实质的时间动力学和炎症特征。 TBI 将按照目标 1 进行诱导，但使用 CX3CR1+/GFPCCR2+/RFP 小鼠除外。将检查受伤后的多个时间点，包括急性期、亚急性期和慢性期。初步数据显示，受伤后 48 小时，接受 TBI 治疗的小鼠巨噬细胞浸润显着增加，并且其中的特定子集类似于常驻小胶质细胞。 我们的研究将提供有关外周巨噬细胞积累在 TBI 诱导的神经炎症致病性中的作用的关键和新颖的信息，并可能提供新的治疗靶点和最佳治疗时间点。